Abstract 15719: Proteomic Analyses Reveal Mechanistic Links Between Clonal Hematopoiesis of Indeterminate Potential and Coronary Artery Disease

Abstract

Introduction: Clonal hematopoiesis of indeterminate potential (CHIP) is a phenomenon where hematopoietic stem cells acquire leukemogenic mutations without blood cancer. CHIP is a causal risk factor for coronary artery disease (CAD), yet underlying mechanisms remain unclear. The plasma proteome may provide novel mechanistic insights into the links between CHIP and CAD. Methods: We studied the associations of CHIP with the plasma proteins and CAD risk in four Trans-Omics for Precision Medicine (TOPMed) longitudinal cohorts: ARIC (N=9,084), CHS (N=1,727), JHS (N=1,858), and MESA (N=978). CHIP (variant allele fraction >2%) was identified from whole genome sequences of blood DNA and modeled both as a composite of the most common drivers ( DNMT3A , TET2 , ASXL1 , and JAK2 ) and separately. Levels of ~1,300 serum proteins measured by SomaScan were log-transformed and residualized on study-specific covariates. The association between CHIP and protein levels was estimated across all participants within each study, as well as by sex, and meta-analyzed. For proteins significantly (FDR<0.05) associated with CHIP, pathway analysis and functional validation in Tet2-/- mice were conducted. Results: Across all studies (mean age: 59.8 y; 43.6% male), 720 (5.6%) individuals were identified with CHIP. There were 143 significant CHIP-protein pairs, with carbonic anhydrase 1, lysozyme C, and properdin being the most associated proteins. TET2 had the largest number of, and strongest, associations among examined driver genes. In sex-stratified analysis, follicle-stimulating hormone was inversely associated in females. Pathway analysis implicated the inflammation-related STAT3 and IL-17 signaling pathways. We observed significantly greater expression of Cfp and Lyz (encoding properdin and lysosome C, respectively) in the monocytes of Tet2 -/- female mice compared to wild-type female mice and Tet2 -/- male mice. A number of proteins (including PCSK9) were significantly associated with both CHIP and CAD, suggesting both shared and nonshared mechanisms. Conclusions: CHIP, particularly TET2 , is broadly associated with plasma proteins, as validated by evidence in Tet2-/- mice. Further studies are needed to understand the biological mechanisms linking CHIP to CAD.